The scabronines, metabolites from the bitter mushroom Sarcodon scabrosus, are related to a broader class of angularly fused tricyclic diterpenoids known as cyathanes (Kita et al. Tetrahedron 54:11877, 1998; incorporated herein by reference). The scabronines are distinct from other cyathanes by an angular C17 carboxyl group rather than a C17 methyl group. A report by Ohta disclosed that scabronine G induces the production and excretion of nerve growth factor (NGF) in human astroglial cells 1321N1 (Obara et al. Mol. Pharmacol. 59:1287, 2001; incorporated herein by reference). The methyl ester derivative of scabronine G is even more active in promoting excretion of NGF and an additional neurotrophin, interleukin 6 (IL-6). Consistent with these biochemical markers, dramatic neuronal differentiation of rat pheochromocytoma cells (PC-12) was observed. Accordingly, scabronine G and its methyl ester fall into a class of non-peptidyl structures exhibiting neurotrophic properties (Hefti et al. Annu. Rev. Pharmacol. Toxicol. 37:239, 1997; Luu et al. Molecules 5:1439, 2000; each of which is incorporated herein by reference).

Naturally occurring polypeptidyl neurotrophic factors play a central role in mediating neuronal growth and survival (Dawbarn et al Neuropath. Appl. Neurobiol 29:211, 2003; incorporated herein by reference). The study of the mechanism of action of these factors (cf. NGF and BDNF) is one of the central challenges in neuroscience. The clinical application of naturally occurring polypeptidyl neurotrophic factors in reversal of neurodegenerative disorders (cf. Parkinson's and Alzheimer's Diseases) has been investigated. However, unfavorable pharmacokinetics require their direct infusion into appropriate sectors of the brain, thus seriously complicating their progression to medical application (Kirik et al. Nat. Neurosci. 7:105, 2004; incorporated herein by reference).
One of the goals of research in this area is to identify promising small molecules with neurotrophic activity. In order to identify such small molecules, a total synthesis of scabronine G would be useful in preparing and identifying small molecules such as analogues of scabronine G with neurotrophic activity or other useful biological activities.